Biologically active peptides

ABSTRACT

There is disclosed biologically active peptides of the formula ##STR1## where X is a hydrogen atom, an N-terminus protecting group (any of an acyl-type protecting group, an aromatic urethane-type protecting group, an alkyl-type protecting group, or an alkyl urethane type protecting group), or a residue of a natural L-amino acid or a dipeptide formed of two natural L-amino acids, wherein the free amino group may be replaced by any of the foregoing N-terminus protecting groups; 
     Y is a hydrogen atom or a protecting group for the phenolic hydroxyl group of tyrosine; 
     A is a D-amino acid residue with a lower (thio) alkyl side chain; 
     B is a neutral L-amino acid residue, a glycine residue, or an N-methyl amino acid residue; 
     C is a direct bond or an amino acid or di-or tripeptide residue; and 
     W is OH, OR, NH 2 , NHR, N(R) 2 , NH-NH 2 , where R is an alkyl, cycloalkyl or aralkyl group of 1 to 7 carbon atoms or NHNHR&#39; where R&#39; is a hydrogen atom, linear or branched alkyl, cycloalkyl; alkenyl, a linear or branched or cyclic aliphatic urethane-type group, an aromatic urethane-type group normally used in polypeptide chemistry, a residue of an α-amino; α-imino, or β-amino acid, or a di-or tripeptide residue, where the -NHR&#39; bond is an amidic linkage and the amino group is free or protected by an N-terminus protecting group. The peptides have central nervous system activity and are useful as analgesics, psychotics, and neuroendocrinologicals.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of copending application Ser.No. 120,832 filed Feb. 12, 1980, now abandoned.

GENERAL DESCRIPTION OF THE INVENTION

The present invention relates to new biologically active peptides, theirpharmaceutically acceptable salts, processes for their preparation, andtheir application as therapeutic agents.

The invention relates more particularly to peptides of the generalformula: ##STR2## wherein:

X is a hydrogen atom, an N-terminus protecting group selected from thegroup consisting of acyl-type protecting groups, aromatic urethane-typeprotecting groups, alkyl-type protecting groups, alipha ticurethane-type protecting groups, or, alternatively, a residue of anatural L-amino acid or a dipeptide from two natural L-amino acids, inwhich the free amino group may be replaced by any of the N-terminusprotecting groups cited above;

Y is a hydrogen atom, or a protecting group for the phenolic hydroxylgroup of tyrosine selected from the group consisting oftetrahydropyranyl, methyl, tert-butyl, trityl, benzyl,2,4-dichlorobenzyl, benzyloxycarbonyl, 2-bromobenzyloxycarbonyl,tert-butyl oxycarbonyl, or lower acyl;

A is a D-amino acid residue with a side chain constituted by a loweralkyl or lower thioalkyl group;

B is a neutral L-amino acid residue, a glycine residue, or an N-methylamino acid residue, such as sarcosine and L-N-methylphenylalanine;

C is a direct bond or a residue of an amino acid or a residue of a di-or tripeptide, and may be of α-amino, α-imino or β-amino acids, ofeither L or D configuration, provided they are not basic or acidic, andin the case of hydroxy amino acids such as tyrosine, serine, andthreonine, the hydroxy group may be free or protected by one of theprotecting groups referred above under Y; and

W is OH, OR, NH₂, NHR, N(R)₂, NH--NH₂, where R is an alkyl, cycloalkyl,or aralkyl group having from 1 to 7 carbon atoms or NHNHR' wherein R' isa hydrogen atom, a C₁ -C₁₀ linear or branched alkyl, cycloalkyl,including adamantyl, or aralkyl group; an alkenyl group having from 2 to8 carbon atoms, a linear, branched, or cyclic aliphatic acyl-type grouphaving from 1 to 16 carbon atoms, unsubstituted or substituted byhydroxy, amino, C₁ -C₄ alkoxy or halogen atom, an aromatic acyl-typegroup, such as benzoic, phenylacetic, and cinnamic residue,unsubstituted or substituted by hydroxy, amino, halogen atom or C₁ -C₄alkoxy; a linear, branched, or cyclic C₃ -C₄ alkoxy; a linear, branched,or cyclic C₃ -C₁₁ aliphatic urethane-type group; an aromaticurethane-type group normally used in polypeptide chemistry, such asbenzyloxy carbonyl; a residue of an α-amino acid, α-imino or β-aminoacid, having either L or D configuration, or a residue of a di- ortripeptide, formed by α-amino, α-imino or β-amino acids, having either Lor D configuration, where the bond ##STR3## is an amidic linkage and theamino group of the residue may be free or protected by an N-terminusprotecting group as defined supra.

Salts of the compounds of general formula (I) with trifluoroacetic acid,hydrofluoric acid, hydroboric acid, acetic acid, and hydrochloric acidas well as other pharmaceutically acceptable salts of compounds ofgeneral formula (I) are all within the scope of the present invention.

The synthesis of the peptides of the present invention may beaccomplished by classical solution methods or by solid phase orpolymeric supports. Examples of both procedures are given below. In theclassical solution method, the synthesis consists essentially inappropriate successive condensations of protected amino acids orpeptides. The condensation is carried out so that the resulting peptideshave the desired sequence of 4-7 amino acid residues. The amino acidsand peptides, which are condensed according to the method known per sein polypeptide chemistry, have their amino and carboxyl groups, whichare not involved in the formation of the peptide linkage, blocked by asuitable protecting group.

The hydroxyl functions of hydroxylated amino acids may be protected bysuitable protecting groups (throughout all the synthesis or only duringa few steps) or they may be left unprotected. The protecting groups arecapable of being removed by acidolysis, saponification, orhydrogenolysis. For the protection of the amino groups the followingprotective groups may for example be employed: benzyloxycarbonyl (Z),t-butyloxycarbonyl(Boc), tritylformyl, trifluoroacetyl ando-nitrophenylsulphenyl.

For the protection of the carboxyl groups the following protectivegroups may for example be employed: methyl, ethyl, tert-butyl, benzyl,and p-nitrobenzyl.

For the protection of the hydroxy groups the following protecting groupsmay for example be used: acetyl, tert-butyloxycarbonyl,benzyloxycarbonyl, 2-bromo-benzyloxycarbonyl, tetrahydropyranyl,tert-butyl, trityl, benzyl, and 2,4-dichlorobenzyl.

The condensation between an amino group of one molecule and a carboxylgroup of another molecule to form the peptidic linkage may be carriedout through an activated acyl-derivative such as a mixed anhydride, anazide, an activated ester, and so on, or by direct condensation betweena free amino group and a free carboxyl group, in the presence of acondensing agent such as dicyclo-hexyl-carbodimide, alone or togetherwith a racemization preventing agent, such as N-hydroxysuccinimide or1-hydroxybenzotriazole.

Hydrazido or substituted hydrazido derivatives in accordance with thepresent invention are prepared by (1) condensing the N-protected peptideor aminoacid with a suitably substituted hydrazine, such asbenzylcarbazate, t-butylcarbazate, adamantyl-carbazate, phenylhydrazine,or adamantylhydrazine, or (2) reacting the N-protected peptide oraminoacid hydrazide with a suitable alkylating agent, such as an alkylchloride, or with a suitable acylating agent such asbenzylchloroformate, t-butylchloroformate, and adamantyl fluoroformate.The condensation may be carried out in a solvent such asdimethylformamide, pyridine, acetonitrile, tetrahydrofuran, and so on.

The reaction temperature may range between -30° C. and room temperature.The reaction time is generally from 1 to 120 hours.

The scheme of synthesis, the protecting groups, and the condensingagents are all selected so to avoid the risk of racemization.De-protecting reactions are carried out according to the methods knownper se in polypeptide chemistry.

In the solid-phase method a polymeric support is used. The polymer ispreferably a copolymer of styrene with 1-2 weight percent ofdivinylbenzene as a cross-linking agent which causes the polystyrenepolymer to be completely insoluble in most organic solvents.

The synthesis is commenced from the C-terminal end of the peptide, byattaching the required amino acid to a chloro-methylated resin, ahydroxymethyl resin, or a benzhydrylamine resin.

The amino and side-chain protecting groups are those described in theclassical solution synthesis.

In the preparation of the compounds of this invention, anamino-protected amino acid is coupled to the chloromethylated resin withthe aid of, for example, cesium bicarbonate catalyst, or to ahydroxymethyl or benzhydrylamine resin with the aid of a condensingagent such as dicyclohexylcarbodiimide.

After the initial coupling, the amino-protecting group is removed by achoice of reagents including trifluoroacetic acid or hydrochloric acidsolutions in organic solvents at room temperature. After removal of theamino-protecting group, the remaining protected amino acids are coupledstepwise in the desired order to obtain the desired peptide.

Each protected amino acid is generally reacted in a 3-fold excess usingan appropriate carboxyl group activator such as dicyclohexylcarbodiimidein solution, for example, methylene chloride-dimethylformamide mixtures.

After the desired amino acid sequence has been completed, the desiredpeptide is removed from the resin support by treatment with a reagentsuch as hydrogen fluoride, which not only cleaves the peptides from theresin, but also cleaves most of the remaining side-chain protectinggroups. When a chloromethylated or hydroxymethylated resin is used, thehydrogen fluoride treatment results in the formation of the free peptideacid (W=OH). When a benzhydrylamine resin is used, the hydrogen fluoridetreatment results directly in the free peptide amide (W=NH₂).Alternatively, when the chloromethylated or hydroxymethylated resin isemployed, the side-chain protected peptide can be cleaved by treatmentof the peptide resin with ammonia or an alkyl or dialkylamine to givethe desired side-chain protected amide, alkylamide or dialkylamide(W=NH₂, NHR, NR₂). The side-chain protection may then be removed by anyof the methods known in the art.

In preparing the esters of the present invention (W=OR), the resins usedto prepare the acid (W=OH) are employed and the side-chain protectedpeptide is cleaved with a base and the appropriate alcohol. Theside-chain protection is then removed in the usual way.

Alternatively, the peptide acids and amides can be obtained from thepeptide esters by saponification or ammonolysis.

DETAILED DESCRIPTION OF THE INVENTION

When X is an acyl-type protecting group, it is conveniently formyl,acetyl, trifluoroacetyl, propionyl, or benzoyl; when X is an aromaticurethane-type protecting group, it is conveniently benzyloxycarbonyl;2,4-dichlorobenzyloxy-carbonyl, 2-bromobenzyloxycarbonyl,4-nitro-benzyloxycarbonyl; or 4-methoxybenzyloxycarbonyl; when X is analiphatic urethane-type protecting group, it is convenientlytert-butyloxycarbonyl, 1-methylcyclobutyloxycarbonyl,adamantyloxycarbonyl and isobornyloxycarbonyl; when X is an alkyl-typeprotecting group, it is conveniently trityl, benzyl, methyl, ethyl, orisopropyl; when X is a natural L-amino acid residue, it is preferablyselected from the group consisting of Gly, Ala, Leu, Met, Lys, Arg, His,Phe, Trp, Ser, and Thr; when X is a dipeptide from two natural L-aminoacids, it is preferably from two L-amino acids selected from the groupcited hereinabove and conveniently it is Arg-Arg, Arg-Lys, Lys-Arg,Lys-Lys, Leu-His, His-Leu, Leu-Leu, Leu-Met, Met-Leu, Leu-Trp, Trp-Leu,Thr-Ala, Ala-Thr, Ser-Ala, and Ala-Ser.

A is preferably a D-amino acid residue selected from the groupconsisting of ala, val, ile, leu, pro, ser, thr, met, met-sulphoxide,and S-ethyl-homocysteine. The small letters indicate D-amino acidresidues.

B is a neutral L-amino acid residue conveniently selected from the groupconsisting of α-aminophenylacetic acid (Phg), Ala, Val, Ile, Leu, Pro,Met, Ser, Thr, Phe, Tyr, Trp, a glycine residue or an N-methylaminoacidresidue, such as sarcosine, L-N-methylalanine, andL-N-methyl-phenylalanine.

C may be direct bond or a residue of an amino acid or a residue of a di-or tripeptide, and may be of (1) an α-amino acid residue, convenientlyselected from the group consisting of Gly, Ala, Val, normal valine(Nva), Leu, Ile, α-amino-n-butyric acid (Abu), Phg, Phe, Trp, Tyr, Ser,Thr, Homoserine (Hse), Met, Met-sulfoxide, β-cyclohexylalanine, andpara-substituted Phe, the substituent being selected from the groupconsisting of chlorine, bromine, fluorine, amino and nitro; (2) anα-imino acid, conveniently selected from the group consisting of Pro,3-hydroxyproline, 4-hydroxyproline, pipecolic acid,2-azetidinecarboxylic acid, 4-thiazolidine carboxylic acid, Δ³ -proline;(3) a β-amino acid, conveniently selected from the group consisting ofβ-alanine, β-phenyl-β-aminopropionic acid, β-aminobutyric acid; (4) anN-methyl amino acid residue, conveniently selected from the groupconsisting of Sar, N-methyl-phenylalanine (MePhe), N-methylalanine(MeAla); all of either L or D configuration, provided they are not basicor acidic; of (5) a dipeptide which may be conveniently selected fromdipeptides resulting from the condensation of α-amino, β-amino, α -iminoand N-methyl amino acids which are as hereinabove defined, provided thatthe two amino acids are not the same; of (6) a tripeptide residue whichmay be conveniently selected from tripeptides J-L-M wherein (a) J isTyr, Trp, Phe, Phg, hexahydro-Phe, Gly, Val and para-substituted Phe,the substituent being selected from the group consisting of chlorine,bromine, fluorine, amino, and nitro, (b) L is Val, Leu, Ile, Gly, Ala,Nva, Sar, MePhe, MeAla, and β-amino or α-imino acids which arehereinabove defined, and (c) M is Ser, Hse, Thr, Abu, or Gly providedthat J is different from L and L is different from M.

Hydroxyamino acids are unprotected or protected by a protecting groupfor the hydroxy function. Suitable protecting groups are methyl,tert-butyl, trityl, benzyl, 2,4-dichlorobenzyl, benzyloxycarbonyl,2-bromobenzyloxycarbonyl, tert-butyloxycarbonyl, or lower acyl,conveniently formyl, acetyl, trifluoroacetyl, propionyl, and benzoyl.

W is OH, OR, NH₂ NHR, N(R)₂, or NHNHR', wherein R is a C₁ -C₁₀ linear orbranched alkyl, conveniently methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, iso-butyl, and 2,2,2 trifluoro ethyl, C₁ -C₁₀cycloalkyl, conveniently cyclohexyl or adamantyl, or C₆ -C₈ aralkyl,conveniently phenyl, benzyl or phenylethyl; and R' is a hydrogen atom, aC₂ -C₁₀ linear or branched alkyl, cycloalkyl or C₆ -C₈ aralkyl,conveniently as hereinabove defined under R, an alkenyl group havingfrom 2 to 8 carbon atoms, preferable allyl; a linear, branched, orcyclic aliphatic acyl-type group having from 1 to 16 carbon atoms,conveniently formyl, acetyl, propionyl, butyryl, lauryl, and1-adamantancarbonyl, unsubstituted or substituted by hydroxy, amino, C₁-C₄ alkoxy, or halogen atom, (a valuable example of this substitutedaliphatic acyl-type group is trifluoroacetyl), an aromatic acyl-typegroup, such as benzoyl, phenylacetyl, and cinnamyl residue,unsubstituted or substituted by hydroxy, amino, halogen atom or C₁ -C₄alkoxy; a linear, branched or cyclic C₃ -C₁₁ aliphatic urethane-typegroup, conveniently as defined under X, and an aromatic urethane-typegroup conveniently as defined under X.

When Y is lower acyl, it is conveniently formyl, acetyl,trifluoroacetyl, propionyl, or benzoyl.

The Rf values are determined on precoated plates of silica gel 60 F₂₅₄(Merck), layer thickness 0.25 mm, length of the plate 20 cm, using thefollowing development systems:

System A: benzene-ethyl acetate-acetic acid-water (10:10:2:1) (upperphase)

System B: benzene-ethyl acetate-acetic acid-water (100:100:40:15) (upperphase)

System C: n-butyl alcohol-acetic acid-water (4:1:1)

System D: chloroform-methyl alcohol--32% ammonium hydroxide (65:45:20)

Symbols herein are those commonly used in peptide chemistry. In thefollowing examples D-amino acid residues are designated by smallletters, e.g., ala=D-Ala; Adoc represents adamatyloxycarbonyl, and Adrepresents adamantyl.

TLC analyses are carried out under no standard conditions, the Rf valuescan therefore change, particularly at different temperatures. Meltingpoints are determined in open capillaries and are uncorrected. Most ofthe derivatives soften and decompose (dec.) before melting. Solvents forcrystallization, precipitation, or grinding are reported in brackets.

High voltage paper electrophoresis is carried out with aPherograph-Original-Frankfurt Type 64 apparatus on Schleicher and Schullpaper No. 2317 at pH 1.2 (formic acid-acetic acid-water 123:100:777) at1600 V (40 V/cm) and at pH 5.8 (pyridine-acetic acid-water 450:50:4500)at 1400 V (32.5 V/cm). Electrophoretic mobilities (E 1.2 and E 5.8) aregiven relative to that of glutamic acid.

The compounds of general formula (I) show interesting pharmacologicalactivities in tests carried out on laboratory animals. Moreparticularly, the compounds of general formula (I) show activity on thecentral nervous system as analgesics, antipsycotics, andneuroendocrinologicals.

Analgesic activity has been assessed in mice by the tailpinch test, asdescribed by HAFFNER in Deutsch.Med.Worschr., 55:731, 1929. The testedsubstances were administered by i.v., s.c., i.p., or oral route. Whenadministered by i.v. or s.c., the tested products displayed an analgesiceffect at doses generally from 0.2 to 50 mg/kg.

The compounds of general formula (I) show receptorial affinities tocentral analgesic drugs when tested "in vitro" on rat brain according tothe procedure described by PERT and SNYDER in Molec.Pharmacol., 10, 878,1974. According to these properties the compounds of general formula (I)may find a therapeutic application for treatment of pains.

The compounds of general formula (I) also display activity on thecentral nervous system with the characteristic properties ofantipsychotic drugs, as shown by tests carried out on rats according tothe procedure described by JANSSEN, JAGENEAU, and SCHELLEKENS inPsychopharmacologia (Berl,), 1, 389, 1960. Active doses are generallyfrom 0.2 to 60 mg/kg. According to this activity, the compounds ofgeneral formula (I) may find a therapeutic application as antipsychoticdrugs.

The compounds of general formula (I) stimulate, among others, therelease of growth-hormone and of prolactin as shown by ratio-immunoassays in the rat which were carried out according to the proceduredescribed by NISWENDER, CHEN, MIDGLEY, METTES, and ELLIS,Proc.Soc.Exp.Biol.Med., 130, 793, 1968. Active doses are generally from0.01 to 10 mg/kg. According to this activity, the compounds of generalformula (I) may find a therapeutic application for stimulating therelease of growth-hormone and prolactin.

Accordingly, therapeutic applications of the compounds of generalformula (I) are also within the scope of the present invention. Fortherapeutic purposes, the compounds of general formula (I) and theirsalts are administered together with conventional pharmaceuticallyacceptable carriers or diluents.

The following examples are illustrative of the compounds of the presentinvention and are not limitative.

EXAMPLE 1 Preparation of H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH₂.CF₃ COOH (13)Step 1. Boc-Pro-Ser-NH₂ (1)

To a solution of 1.00 g (4.65 mmoles) Boc-Pro-OH in 10 ml anhydroustetrahydrofuran, 0.52 ml (4.65 mmoles) N-methylmorpholine, and 0.45 ml(4.65 mmoles) ethyl chloroformate are successively added at atemperature of -12° C. After stirring at this temperature for 2 minutes,a cold solution of 0.48 g (4.65 mmoles) H-Ser-NH₂ (R. W. Hanson and H.N. Rydon, J. Chem. Soc., 836, 1964) in 10 ml dimethylformamide is added.The reaction mixture is stirred at -10° C. for 3 hours and at 20° C. for1 hour, then filtered from salts and evaporated in vacuo. The residue istaken up with tetrahydrofuran, filtered, and the solution evaporatedagain in vacuo. By crystallization from methanol-diethylether 1.1 g ofcompound (1) are obtained: m.p. 138° C. [α]_(D) ²⁵ -58.9° (c=1, MeOH);Rf_(A) =0.15; Rf_(B) =0.33.

Step 2. H-Pro-Ser-NH₂.CF₃ COOH (2)

1.0 g. (3.3 mmoles) Boc-Pro-Ser-NH₂ (1) is dissolved in 10 mltrifluoroacetic acid at 0° C. After 30 minutes at 0° C. the solution isevaporated in vacuo, diluted with methanol, and evaporated again invacuo. The product (2) is isolated from diethylether-petroleum ether:1.0 g, m.p. 48°-50° C.; Rf_(C) =0.10.

Step 3. Boc-Tyr (Bzl)-Pro-Ser-NH₂ (3)

A solution of 1.0 g (3.2 mmoles) H-Pro-Ser-NH₂.CF₃ COOH (2) in 35 mldimethylformamide is cooled at 0° C., then 0.36 ml (3.2 mmoles)N-methyl-morpholine are added, followed by 1.2 g (3.2 mmoles) Boc-Tyr(Bzl)-OH, 0.43 g (3.2 mmoles) 1-hydroxybenzotriazole, and 0.73 g (3.52mmoles) dicyclohexylcarbodiimide. The reaction mixture is stirred for 1hour at 0° C. and at room temperature overnight, then it is filtered,and evaporated in vacuo. The residue is dissolved in ethyl acetate andthe solution washed successively with NaCl-saturated solutions of 1 Mcitric acid, 1 M NaHCO₃, and water. The organic solution is dried overanhydrous Na₂ SO₄ and the solvent removed in vacuo. The (3) product isrecovered by crystallization from ethyl acetate-petroleum ether: 1.4 g,m.p. 115° C.; [α]_(D) ²⁵ -22.9° (c=1, MeOH); Rf_(A) =0.20

Step 4. H-Tyr (Bzl)-Pro-Ser-NH₂.CF₃ COOH (4)

Operating as in Step 2, from 1.0 g (1.8 mmoles) Boc-Tyr(Bzl)-Pro-Ser-NH₂ (3) 1.0 g of compound (4) are obtained; [α]_(D) ²⁵-7.4° (c=1, MeOH); Rf_(C) =0.59; m.p. 54°-57° C. (dec.)

Step 5. Boc-Phe-Gly-NH-NH-Z (5)

0.42 ml (3.8 mmoles) N-methylomorpholine and 0.3 ml (3.8 mmoles)ethylchloroformate are successively added at -12° C. to a solution of1.0 g (3.8 mmoles) Boc-Phe-OH in 10 ml anhydrous tetrahydrofuran. Afterstirring at this temperature for 2 minutes, a cold solution of 0.95 g(3.7 mmoles) H-Gly-NH-NH-Z.HCl (K. Hoffmann et al, J. Amer, Chem, Soc.94, 6171, 1972) and 0.4 ml (3.7 mmoles) N-methylmorpholine in 15 mldimethylformamide is added. The reaction mixture is stirred at -10° C.for 3 hours and at 20° C. for 1 hour, then filtered from salts andevaporated in vacuo. The residue is dissolved in ethyl acetate andwashed several times successively with NaCl-saturated solutions of 1 Mcitric acid, 1 M NaHCO₃, and water. The organic layer is dried overanhydrous Na₂ SO₄ and the solvent removed in vacuo. The product (5) (1.4g) is recovered from methanol-diisopropyl ether: m.p. 143° C.; [α]_(D)²⁵ +5.6° (c=1, MeOH); Rf_(A) =0.63.

Step 6. H-Phe-Gly-NH-NH-Z.HCl (6)

1.0 g (2.1 mmoles) Boc-Phe-Gly-NH-NH-Z (5) is treated for 30 minutes atroom temperature with 10 ml of a 1.3 N solution of hydrogen chloride inglacial acetic acid. Removal of the solvent in vacuo at 30° C., andgrinding of the residue with diethylether, gives 0.89 of (6), m.p. 178°C.; [α]_(D) ²⁵ +45° (c=1, MeOH); Rf_(C) =0.78; E₁.2 =0.88.

Step 7 Boc-ala-Phe-Gly-NH-NH-Z (7)

Starting from 1.0 g (5.3 mmoles) Boc-ala-OH and 2.09 g (5.1 mmoles)H-Phe-Gly-NH-NH-Z.HCl (6), and operating as in Step 5, compound (7) (2.5g) is obtained from methanol-diisopropyl ether: m.p. 165° C.; [α]_(D) ²⁵+8° (c=1, MeOH); Rf_(A) =0.51.

Step 8. H-ala-Phe-Gly-NH-NH-Z.HCl (8)

Starting from 1.0 g (1.8 mmoles) Boc-ala-Phe-Gly-NH-NH-Z (7) andoperating as in Step 6, 0.84 g of (8) are obtained: m.p. 180° C.;[α]_(D) ²⁵ +0.2° (c=1, MeOH); Rf_(C) =0.75. E₁.2 =0.80.

Step 9. Boc-Tyr-ala-Phe-Gly-NH-NH-Z (9)

Starting from 1.0 g (3.5 mmoles) Boc-Tyr-OH and 1.65 g (3.4 mmoles)H-ala-Phe-Gly-NH-NH-Z.HCl (8) and operating as in Step 5, 2.24 g of (9)are obtained (crystallization from methanol-diisopropyl ether); m.p.148° C.; [α]_(D) ²⁵ +16.2° (c=1, MeOH); Rf_(A) =0.38.

Step 10. Boc-Tyr-ala-Phe-Gly-NH-NH₂ (10)

1.0 g (1.4 mmoles) Boc-Tyr-ala-Phe-Gly-NH-NH-Z (9) in 10 ml methanol ishydrogenated at room temperature in the presence of 0.27 g 10% Pd/C. Thecatalyst is removed by filtration and the solution concentrated invacuo. By dilution with ethyl acetate 0.64 g of compound (10) isobtained, m.p. 148° C.; [α]_(D) ²⁵ +26.6° (c=1, MeOH); Rf_(B) =0.34.E₁.2 =0.57.

Step 11. Boc-Tyr-ala-Phe-Gly-Tyr (Bzl)-Pro-Ser-NH₂ (11)

To a solution of 2.0 g (3.5 mmoles) Boc-Tyr-ala-Phe-Gly-NH-NH₂ (10) in20 ml anhydrous dimethylformamide, 2.18 ml (8.75 mmoles) 4 N hydrogenchloride in anhydrous tetrahydrofuran and 0.45 ml (3.85 mmoles) n-butylnitrite are successively added at a temperature of -30° C. Afterstirring at this temperature for 30 minutes, 1 ml (8.75 mmoles)N-methylmorpholine is added, followed by a cold solution (-30° C.) of1.66 g (2.91 mmoles) H-Tyr (Bzl)-Pro-Ser-NH₂.CF₃ COOH (4) and 0.33 ml(2.91 mmoles) N-methylmorpholine in 40 ml dimethylformamide. Thereaction mixture is allowed to react at -9° C. for three days, then thesalts are filtered off, the solvent is removed in vacuo, and the productis precipitated from methanol-ethyl acetate-diethyl ether. The crudeproduct is purified by column chromatography on silica gel (Merck),70-230 mesh, eluting with ethyl acetate-methanol (8:2), 2.0 g of (11)are obtained from methanol-diethyl ether; m.p. 135° C.; [α]_(D) ²⁵ -5.3°(c=1, MeOH); Rf_(B) =0.24.

Step 12. Boc-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH₂. (12)

1.3 g (1.3 mmoles) Boc-Tyr-ala-Phe-Gly-Tyr (Bzl)-Pro-Ser-NH₂ (11)dissolved in 20 ml methanol are hydrogenated at 35° C. in the presenceof 0.30 g 10% Pd/C. The catalyst is removed by filtration, and thesolution is concentrated in vacuo. By dilution with diethyl ether 1.1 gof compound (12) are obtained, m.p. 160°-163° C. (dec.), [α]_(D) ²⁵-7.6° (C=1, MeOH); Rf_(B) =0.11; Rf_(C) =0.80.

Step 13. H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH₂. CF₃ COOH (13)

1.0 g (1.1 mmoles) Boc-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH₂ (12) is treatedfor 30 minutes at 0° C. with 10 ml trifluoroacetic acid. The solvent isremoved in vacuo and the residue is ground with diethyl ether, giving0.90 g of (13), m.p. 159°-160° C. [α]_(D) ²⁵ +5.5° (C=1, MeOH); Rf_(C)=0.51.

EXAMPLE 2 Preparation of H-Tyr-ala-Phe-Gly-Tyr-NH₂.CF₃ COOH (15) Step 1.Boc-Tyr-ala-Phe-Gly-Tyr-NH₂ (14)

2.74 g (4.8 mmoles) Boc-Tyr-ala-Phe-Gly-NH-NH₂ (10) are dissolved in 50ml anhydrous dimethylformamide and cooled at -30° C. 2.0 ml (12 mmoles)6 N hydrogen chloride in anhydrous tetrahydrofuran and 0.63 ml (5.28mmoles) n-butyl nitrite are successively added and the reaction mixtureis stirred for 30 min. at -30° C. 1.34 ml (12 mmoles)N-methyl-morpholine are added at -40° C., followed by a precooled (-40°C.) solution of 0.865 g (4.0 mmoles) H-Tyr-NH₂.HCl (K. Blau and S. G.Waley, Biochem. J., 57, 538, 1954) and 0.456 ml (4.0 mmoles)N-methylmorpholine in 50 ml dimethylformamide. The reaction mixture isallowed to react for 7 days at -10° C., then it is concentrated to smallvolume, filtered from salt, and the product precipitated by dilutionwith chloroform. By crystallization from methyl alcohol-chloroform, 2.0g of (14) are obtained, m.p. 127°-129° C.; [α]_(D) ²⁵ +19.9° (C=1,MeOH); Rf_(A) =0.15, Rf_(B) =0.56.

Step 2. H-Tyr-ala-Phe-Gly-Tyr-NH₂.CF₃ COOH (15)

1.0 g (1.4 mmoles) Boc-Tyr-ala-Phe-Gly-Tyr-NH₂ (14) is made to reactwith 12 ml trifluoroacetic acid for 30 min. at 0° C. The acid isevaporated in vacuo, and the residue ground with diethyl ether. Bycrystallization from isopropyl alcoholdiisopropyl ether, 0.94 g of (15)are obtained, m.p. 145°-146° C.; [α]_(D) ²⁵ +34.5° (C=1 MeOH); Rf_(C)=0.65.

Solid-phase synthesis. The synthesis on a polymeric support can becarried out, for example, by one of the following procedures:

Procedure A. Preparation of Boc-(AA)_(n) -(AA)_(n-1) . . . (AA)Hydroxymethyl Polystyrene Ester

Chloromethylated polystyrene resin is esterified with the firstBoc-amino acid (Boc-AA₁ -OH) according to Gisin, Helv. Chim. Acta, 56,1476 (1973). The polystyrene ester is treated according to Schedule Afor the incorporation of Boc-(AA)₂ -OH, --Boc-(AA)_(n) -OH to give thetitle resin.

Schedule A

1. Wash with CH₂ Cl₂ ×3;

2. Treat with TFA-CH₂ Cl₂ (1:1) twice for 1 min.;

3. Treat with TFA-CH₂ Cl₂ (1:1) for 30 min.;

4. Wash with CH₂ Cl₂ ×4;

5. Treat with 10% TEA in CH₂ Cl₂ twice for 1 min.;

6. Treat with 10% TEA in CH₂ Cl₂ for 10 min.;

7. Wash with CH₂ Cl₂ ×3;

8. Wash with DMF×3;

9. Wash with CH₂ Cl₂ ×3;

10. Add 2 or 3 equivalents of the symmetrical anhydride of thecorresponding amino acid derivative, prepared as described by Hagenmayerand Frank, Hoppe-Seyler's Z.Physiol.Chem., 353, 1973 (1972), dissolvedin CH₂ Cl₂. Reaction time 1-2 hours.

11. Wash with CH₂ Cl₂ ×3;

12. Wash with isopropyl alcohol×3;

13. Wash with CH₂ Cl₂ ×3;

14. Test ninhydrin reaction according to Kaiser et al, Annal.Biochem.,34, 595 (1970). In case of incomplete reaction repeat procedures 4 to 14as above.

The abbreviations for solvents or reagents employed in Schedule A are asfollows:

TFA: Trifluoroacetic acid.

TEA: Triethylamine

DMF: Dimethylformamide.

Procedure B. Preparation of H-(AA)_(n) -(AA)_(n-1) . . . (AA)₁-Hydroxymethyl Polystyrene Ester

After introduction of the last amino acid derivative according toSchedule A (Procedure A), wash the resin 3 times with acetic acid,repeat procedures 1 to 9, and wash 4 times with isopropyl alcohol.

Procedure C. Preparation of Boc-(AA)_(n) -(AA)_(n-1) . . . (AA)₁-Benzhydrylamine Resin

Boc-(AA)₁ -OH is attached to the benzhydrylamine resin viadicyclohexylcarbodiimide, as described by Pietta et al, J.Org.Chem., 39,44 (1974). Unreacted amino groups are acetylated with aceticanhydride/pyridine/CH₂ Cl₂ (2:1:10). The polystyrene amide is thentreated according to Schedule A (Procedure A) for the incorporation ofthe other amino acid residues to give the title resin.

Procedure D. Preparation of H-(AA)_(n) -(AA)_(n-1) . . . (AA)₁-Benzhydrylamine Resin

Operate as in Procedure B starting from the peptide resin of ProcedureC.

EXAMPLE 3 Preparation of H-Tyr-ala-Phe-Gly-OMe (16)

1 g peptide resin of Procedure B with the required sequence of aminoacid residues (introduced as Boc-Gly-OH, Boc-Phe-OH, Boc-ala-OH andBoc-Tyr-OH, in that order) is suspended in 25 ml methyl alcohol and 2 mltriethylamine for 3 days at room temperature. The resin is filtered off,washed with dimethylformamide, and the solvent evaporated in vacuo. Bycrystallization of the residue from isopropyl alcohol, 0.16 g of thetitle compound (16) is obtained, m.p. 216°-218° C.; [α]_(D) ²⁸ -32.6°(C=1, DMF); Rf_(C) =0.70. Amino acid ratios: Gly 1.04; ala 1.06; Tyr0.99; Phe 1.00.

EXAMPLE 4 Preparation of H-Tyr-ala-Phe-Gly-OH (17)

(i) 1 g of the same peptide resin as in Example 3 is treated for 45 min.at 0° C. with 10 ml anhydrous (distilled over CoF₃) HF containing 1 mlanisole. The hydrogen fluoride is evaporated under reduced pressure andthe anisole is removed by washing with diisopropyl ether. The crudepeptide is extracted from the resin with 50% acetic acid, then purifiedby chromatography on a column of Sephadex G-15 by elution with 0.5 Nacetic acid, and finally transformed into the acetate by treatment withamberlite IRA-45 (CH₃ COO⁻).

(ii) Alternatively, 0.10 g peptide ester (16) are suspended in 5 ml H₂ Oand 3 ml methyl alcohol and saponified with 0.32 ml 1 N NaOH for 90 min.at room temperature. 0.32 ml 1 N HCl are added, and the solutionconcentrated in vacuo. By dilution with 95% ethanol 0.08 g of the titlecompound (17) is obtained, m.p. 250°-252° C. (dec.); [α]_(D) ²⁸ -2.8°(C=1, DMF), Rf_(C) =0.56. Amino acid ratios: Gly 1.04; ala 0.94; Tyr1.00; Phe 1.05.

EXAMPLE 5 Preparation of H-Tyr-ala-Phe-Gly-NH₂ (19)

(i) 1 g of the same peptide resin as in Example 3 is suspended in 10 mlof a (1:1) mixture of methyl alcohol-dimethylformamide, and saturated at0° C. with ammonia. The reaction mixture is stirred for 3 days at roomtemperature, then the resin is filtered off, washed withdimethylformamide, and the solvents evaporated in vacuo. The residue istreated with a solution of hydrogen chloride in anhydroustetrahydrofuran and the product recovered as hydrochloride fromisopropyl alcohol. 0.09 g of the title compound (19) is obtained, m.p.206° C.; [α]_(D) ²⁸ +49.9° (C=1, MeOH), Rf_(C) =0.58. Amino acid ratios:Gly 1.05; ala 1.00; Tyr 0.91; Phe 1.03.

(ii) Alternatively, the same peptide (19) may be obtained from thepeptide resin of Procedure D (with the required sequence of amino acidresidues), by operating in the same way as described in Example 4(i).

By the classical solution procedure the following other derivatives havealso been synthesized:

(20) H-Tyr-ala-Phe-Gly-NH-NH₂.2 HCl m.p. 190°-195° C. (dec.) (diethylether); Rf_(C) 0.50; E₁.2 1.09.

(21) H-Tyr-ala-Phe-Sar-NH-NH₂.2 HCl m.p. 193°-197° C. (dec.)(tetrahydrofuran); Rf_(C) 0.47; E₁.2 1.12.

(22) H-Tyr-ala-Phe-Sar-NH-NH-Z.HCl m.p. 150°-155° C. (dec.) (ethylacetate); Rf_(C) 0.70; E₁.2 0.59.

(23) Boc-Tyr-ala-Phe-Sar-NH-NH₂ m.p. 110°-115° C. (dec.) (ethylacetate-diethyl ether); Rf_(B) 0.32; E₁.2 0.57.

(24) Boc-Tyr-ala-Phe-Phe-NH-NH₂ m.p. 180°-183° C. (dec.) (ethylacetate); Rf_(B) 0.54; E₁.2 0.49.

(25) H-Tyr-ala-Phe-Gly-Tyr-Pro-NH₂.HCl m.p. ca. 200° C. (dec.) (ethylacetate); Rf_(C) 0.58; E₁.2 0.59.

(26) H-Tyr-ala-Phe-Gly-Tyr-(Bzl)-Pro-NH₂.HCl m.p. ca. 180° C. (dec.)(diethyl ether); Rf_(C) 0.63. E₁.2 0.53.

(27) Boc-Tyr-ala-Phe-Gly-Tyr-Pro-NH₂ m.p. 170° C.-175° C. (dec.)(diisopropyl ether); Rf_(B) 0.24.

(28) Boc-Tyr-ala-Phe-Gly-Tyr (Bzl)-Pro-NH₂ m.p. 143° C. (diethyl ether)Rf_(B) 0.47.

(29) H-Tyr-ala-Phe-Gly-Tyr-Ser-NH₂.CF₃ COOH m.p. 150°-153° C. (dec.)(diethyl ether); Rf_(C) 0.59; E₁.2 0.57.

(30) Boc-Tyr-ala-Phe-Gly-Tyr-Ser-NH₂ m.p. ca. 100° C. (dec.) (ethylacetate); Rf_(B) 0.15; Rf_(C) 0.83.

(31) H-Tyr-ala-Phe-Gly-Tyr-Hyp-Ser-NH₂.HCl m.p. 210°-220° C. (dec.)(isopropyl alcohol-diethyl ether); Rf_(C) 0.44; Rf_(D) 0.66; E₁.2 0.51.

(32) H-Tyr-ala-Phe-Gly-Tyr-(Bzl)-Hyp-Ser(Bzl)-NH₂.HCl m.p. 175°-180° C.(dec.) (methyl alcohol-diethyl ether) Rf_(C) 0.67; E₁.2 0.44.

(33) Boc-Tyr-ala-Phe-Gly-Tyr-Hyp-Ser-NH₂ m.p. 156°-160° C. (dec.) (ethylacetate-diethyl ether); Rf_(C) 0.75.

(34) Boc-Tyr-ala-Phe-Gly-Tyr (Bzl)-Hyp-Ser (Bzl)-NH₂ m.p. 130°-136° C.(dec.) (isopropyl alcohol-ethyl acetate); Rf_(B) 0.33; Rf_(C) 0.95.

(35) H-Tyr-ala-Phe-Gly-Tyr-Val-Ser-NH₂.CF₃ COOH m.p. 203°-206° C. (dec.)(diethyl ether) Rf_(C) 0.71; E₁.2 0.51.

(36) Boc-Tyr-ala-Phe-Gly-Tyr-Val-Ser-NH₂ m.p. 230° C. (dec.)(diisopropyl ether); Rf_(E) 0.47.

(37) H-Tyr-ala-Phe-Gly-Tyr-Ser-NH₂.CF₃ COOH m.p. 180°-190° C. (dec.)(diethyl ether); Rf_(C) 0.51; Rf_(D) 0.73; E₁.2 0.52.

(38) Boc-Tyr-ala-Phe-Gly-Tyr-Gly-Ser-NH₂ m.p. 245°-250° C. (dec.)(diethyl ether-petroleum ether); Rf_(C) 0.79.

(39) H-Tyr-ala-Phe-Gly-Phe-Pro-Ser-NH₂.HCl m.p. 190°-195° C. (dec.)(methyl alcohol-diethyl ether); Rf_(D) 0.84; E₁.2 0.52.

(40) Boc-Tyr-ala-Phe-Gly-Phe-Pro-Ser-NH₂ m.p. 155°-160° C. (dec.)(methyl alcohol-ethyl acetate); Rf_(B) 0.16; Rf_(C) 0.80.

(41) H-Tyr-ala-Phe-Gly-Phe-Hyp-Ser-NH₂.HCl m.p. <300° C. (dec.) (methylalcohol-ethyl acetate) Rf_(C) 0.47; Rf_(D) 0.75; E₁.2 0.51.

(42) H-Tyr-ala-Phe-Gly-Phe-Hyp-Ser(Bzl)-NH₂.HCl m.p. 160°-170° C. (dec.)(isopropyl alcohol-ethyl acetate); Rf_(C) 0.65; E₁.2 0.50.

(43) Boc-Tyr-ala-Phe-Gly-Phe-Hyp-Ser-NH₂ m.p. 165°-170° C. (dec.)(methyl alcohol-diethyl ether); Rf_(C) 0.75.

(44) Boc-Tyr-ala-Phe-Gly-Phe-Hyp-Ser (Bzl)-NH₂ m.p. 140°-145° C. (dec.)(isopropyl alcohol-ethyl acetate); Rf_(B) 0.25; Rf_(C) 0.90.

(45) H-Tyr-ala-Phe-Gly-Trp-Pro-Ser-NH₂.HCl m.p. 210°-220° C. (dec.)(isopropyl alcohol-ethyl acetate); Rf_(C) 0.54; Rf_(D) 0.79; E₁.2 0.50.

(46) Boc-Tyr-ala-Phe-Gly-Trp-Pro-Ser-NH₂ m.p. 175°-180° C. (dec.)(methyl alcohol-ethyl acetate); Rf_(B) 0.12; Rf_(C) 0.81; Rf_(D) 0.86.

(47) H-Tyr-ala-Phe-Phe-Tyr-Pro-Ser-NH₂.HCl m.p. 195°-200° C. (dec.)(diethyl ether): Rf_(C) 0.66; Rf_(D) 0.82; E₁.2 0.50.

(48) H-Tyr-ala-Phe-Phe-Tyr (Bzl)-Pro-Ser-NH₂.HCl m.p. 160°-180° C.(dec.) (ethyl alcohol-diethyl ether); Rf_(C) 0.72; Rf_(D) 0.90; E₁.20.46.

(49) Boc-Tyr-ala-Phe-Phe-Tyr-Pro-Ser-NH₂ m.p. 140°-145° C. (diethylether); Rf_(B) 0.18; Rf_(C) 0.88.

EXAMPLE 6 Preparation of H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-NH-Z.Hcl (63)Step 1. Boc-Ser-NH-NH-Z (50)

To a solution of 1.0 g (4.87 mmoles) Boc-Ser-OH in 20 ml anhydroustetrahydrofuran, 0.55 ml (4.87 mmoles) N-methylmorpholine, and 0.49 ml(4.87 mmoles) ethyl chloroformate are successively added at atemperature of -12° C. After stirring at this temperature for 2 minutes,a cold solution of 1.0 g (4.87 mmoles) H₂ N-NH-Z.Hcl and .55 ml (4.87mmoles) N-methylmorpholine in 20 ml dimethylformamide is added. Thereaction mixture is stirred at -10° C. for 3 hours and at 20° C. for 1hour, then filtered from salts and evaporated in vacuo. The residue isdissolved in ethyl acetate and washed several times successively with aNaCl-saturated solution of 1 M citric acid, 1 M NaHCO₃, and water. Theorganic layer is dried over anhydrous Na₂ SO₄ and the solvent removed invacuo. The product is purified by column chromatography on silica geleluted with CHCl₃ :MeOH=98:2. The homogeneous fractions on TLC arecollected and the solvent removed in vacuo. By grinding with diethylether-petroleum ether, 1.4 g of compound (50) are obtained: m.p. 42°-46°C.; [α]_(D) ²⁵ -25.8° (c=1, MeOH); Rf_(A) =0.52.

Step 2. H-Ser-NH-NH-Z.HCl (51)

1.0 g (2.83 mmoles) Boc-Ser-NH-NH-Z (50) is dissolved in 10 ml of a 4 Nsolution of hydrogen chloride in anhydrous tetrahydrofuran at roomtemperature. After maintaining the solution for 30 minutes at roomtemperature, diethylether is added to the solution and the precipitateis filtered. The crude product is recrystallized from absoluteethanol-diethyl ether: there is obtained 0.7 g of compound (51): m.p.110°-115° C.; [α]_(D) ²⁵ +20.7° (c=1, MeOH); Rf_(C) =0.49; E₁.2 =1.16.##STR4##

1.0 g (8.7 mmoles) H-Pro-OH is dissolved at room temperature in 4.35 mlof 2 N NaOH. The solution is then cooled to 0° C., diluted with 10 mldimethylformamide, and the solvents removed in vacuo at 35° C. Theresidue is suspended in 10 ml dimethylformamide and 4.3 g (8.7 mmoles)##STR5## are added. The reaction mixture is stirred for 1 hour at roomtemperature and then evaporated in vacuo. The residue is dissolved inwater and washed several times with ethyl acetate. The aqueous layer iscooled at 0° C., acidified with a 5 N aqueous solution of hydrogenchloride to pH 2, and then extracted with ethyl acetate. The organiclayer is washed to neutrality with NaCl-saturated aqueous solution anddried over anhydrous Na₂ SO₄. Removal of the solvent at 30° C. gives 3.7g of (52), m.p. 97°-100° C. (dec.) [α]_(D) ²⁵ -15.7° (c=1, MeOH); Rf_(A)=0.70; E₅.8 =0.35.

Step 4. Boc-Tyr-Pro-OH (53)

1.0 g (2.13 mmoles) ##STR6## in 15 ml methanol is hydrogenated at 30° C.in the presence of 0.27 g 10% Pd/C. The catalyst is removed byfiltration, the solution is diluted with ethyl acetate and concentratedin vacuo up to precipitation. 0.7 g of compound (53) is obtained, m.p.136°-138° C.; [α]_(D) ²⁵ -25.0° (c=1, MeOH); Rf_(A) =0.42; E₅.8 =0.52.

Step 5. Boc-Tyr-Pro-Ser-NH-NH-Z (54)

Starting from 1.0 g (2.65 mmoles) Boc-Tyr-Pro-OH (53) and 0.77 g (2.65mmoles) H-Ser-NH-NH-Z.HCl (51) and operating as in Step 1, 1.46 g (54)are obtained (crystallization from diethyl ether-petroleum ether); m.p.116°-118° C.; [α]_(D) ²⁵ -46.5° (c=1, MeOH); Rf_(A) =0.17, Rf_(B) =0.37.

Step 6. H-Tyr-Pro-Ser-NH-NH-Z.HCl (55)

Starting from 1.0 g (1.63 mmoles) Boc-Tyr-Pro-Ser-NH-NH-Z (54) andoperating as in Step 2, 0.78 g of (55) are obtained from diethyl ether:m.p. 172°-174° C.; [α]_(D) ²⁵ -38.4° (c=1, MeOH); Rf_(C) =0.46; E₁.2=0.79.

Step 7. Boc-Phe-Gly-NH-NH-Z (56)

Starting from 1.0 g (3.8 mmoles) Boc-Phe-OH and 0.95 g (3.7 mmoles)H-Gly-NH-NH-Z.HCl (K. Hofmann et al., J. Am. Chem. Soc. 94, 6171, 1972)and operating as in Step 1, compound (56) (1.4 g) is recovered frommethanol-diisopropyl ether: m.p. 143° C. [α]_(D) ²⁵ +5.6° (c=1, MeOH);Rf_(A) =0.63.

Step 8. H-Phe-Gly-NH-NH-Z.HCl (57)

1.0 g (2.1 mmoles) Boc-Phe-Gly-NH-NH-Z (56) is treated for 30 minutes atroom temperature with 10 ml of a 1.3 N solution of hydrogen chloride inglacial acetic acid. Removal of the solvent in vacuo at 30° C., andgrinding of the residue with diethyl ether gives 0.89 g of (57), m.p.178° C.; [α]_(D) ²⁵ +45° (c=1, MeOH); Rf_(C) =0.78; E₁.2 =0.88.

Step 9. Boc-ala-Phe-Gly-NH-NH-Z (58)

Starting from 1.0 g (5.3 mmoles) Boc-ala-OH and 2.09 g (5.1 mmoles)H-Phe-Gly-NH-NH-Z.HCl (57), and operating as in Step 5, compound (58)(2.5 g) is obtained from methanol-diisopropyl ether: m.p. 165° C.;[α]_(D) ²⁵ =+8° (c=1, MeOH); Rf_(A) =0.51.

Step 10. H-ala-Phe-Gly-NH-NH-Z.HCl (59)

Starting from 1.0 g (1.8 mmoles) Boc-ala-Phe-Gly-NH-NH-Z (58) andoperating as in Step 6, 0.84 g of (59) are obtained: m.p. 180° C.;[α]_(D) ²⁵ =+0.2° (c=1, MeOH); Rf_(C) =0.75; E₁.2 =0.80.

Step 11. Boc-Tyr-ala-Phe-Gly-NH-NH-Z (60)

Starting from 1.0 g (3.5 mmoles) Boc-Tyr-OH and 1.65 g (3.4 mmoles)H-ala-Phe-Gly-NH-NH-Z.HCl (59) and operating as in Step 5, 2.24 g of(60) are obtained (crystallization from methanol-diispropyl ether); m.p.148° C.; [α]_(D) ²⁵ +16.2° (c=1, MeOH); Rf_(A) =0.38.

Step 12. Boc-Tyr-ala-Phe-Gly-NH-NH₂ (61)

1.0 g (1.4 mmoles) Boc-Tyr-ala-Phe-Gly-NH-NH-Z (60) in 10 ml methanol ishydrogenated at room temperature in the presence of 0.27 g 10% Pd/C.Operating as in Step 4, 0.64 g of compound (61) is obtained, m.p. 148°C.; [α]_(D) ²⁵ +26.6° (c=1, MeOH); Rf_(B) =0.34; E₁.2 =0.57.

Step 13. Boc-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-NH-Z (62)

To a solution of 1 g (1.75 mmoles) Boc-Tyr-ala-Phe-Gly-NH-NH₂ (61) in 15ml anhydrous dimethylformamide, 1.1 ml (4.38 mmoles) 4 N hydrogenchloride in anhydrous tetrahydrofuran and 0.2 ml (1.93 mmoles) n-butylnitrite are successively added at a temperature of -30° C. Afterstirring at this temperature for 30 minutes, 0.5 ml (4.38 mmoles)N-methylmorpholine are added, followed by a cold solution (-30° C.) of0.803 g (1.46 mmoles) H-Tyr-Pro-Ser-NH-NH-Z.HCl (55) and 0.16 ml (1.46mmoles) N-methyl-morpholine in 15 ml anhydrous dimethylformamide. Thereaction mixture is allowed to react at -9° C. for two days; then thesalts are filtered off, the solvent is removed in vacuo, and the productis poured into a 10% citric acid solution cooled at 0° C. Theprecipitate is filtered, washed to neutrality with water and dried invacuo. The product is recrystallized from ethyl acetate-diethyl ether;1.15 g of (62) are obtained: m.p. 140°-150° C.; [α]_(D) ²⁵ -20.3° (c=1,MeOH); Rf_(B) =0.17, Rf_(C) =0.92.

Step 14. H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-NH-Z.HCl (63)

Starting from 1.0 g (0.95 mmoles)Boc-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-NH-Z (62) and operating as in Step 2,0.89 g of compound (63) are obtained from ethyl acetate; m.p. 170° C.(dec.); [α]_(D) ²⁵ +1.8° (c=1, MeOH); [α]_(D) ²⁵ +1.0° (c=1, AcOH);Rf_(C) =0.69; E₁.2 =0.50.

EXAMPLE 7 Preparation of H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Z.HCl (67) Step 1.Boc-Tyr-NH-NH-Z (64)

To a solution of 1.0 g (3.55 mmoles) Boc-Tyr-OH in 20 ml anhydroustetrahydrofuran, 0.4 ml (3.55 mmoles) N-methylmorpholine, and 0.48 ml(3.55 mmoles) iso-butyl chloroformate are successively added at atemperature of -12° C. After stirring at this temperature for 2 minutes,a cold solution of 0.72 g (3.55 mmoles) H₂ N-NH-Z.HCl and 0.4 mlN-methyl morpholine in 20 ml dimethylformamide is added. The reactionmixture is stirred at -10° C. for 90 minutes, then filtered from salts,and evaporated in vacuo. The residue is dissolved in ethyl acetate andwashed several times successively with an aqueous solution of 1 M citricacid, 1 M NaHCO₃, and saturated NaCl. The organic layer is dried overanhydrous Na₂ SO₄, and removal of the solvent gives 1.3 g of compound(64): m.p. 68°-70° C.; [α]_(D) ²⁵ -5.85 (c=2, MeOH); Rf_(A) =0.76.

Step 2. H-Tyr-NH-NH-Z.HCl (65)

1.0 g (2.33 mmoles) Boc-Tyr-NH-NH-Z (64) is dissolved in 10 ml of 4 Nsolution of hydrogen chloride in anhydrous tetrahydrofuran at roomtemperature. After 30 minutes at room temperature the solvent isevaporated in vacuo and the product is precipitated from isopropylalcohol-diethylether; 0.76 g of compound (65) are obtained: m.p.103°-105° C.; [α]_(D) ²⁵ +48.8° (c=1, MeOH); Rf_(C) =0.70; E₁.2 =0.92.

Step 3. Boc-Tyr-ala-Phe-Gly-Tyr-NH-NH-Z (66)

To a solution of 1.0 g (1.75 mmoles) Boc-Tyr-ala-Phe-Gly-NH-NH₂ (61) in15 ml anhydrous dimethylformamide, 1.1 ml (4.38 mmoles) 4 N hydrogenchloride in anhydrous tetrahydrofuran and 0.2 ml (1.93 mmoles) N-butylnitrite are successively added at a temperature of -30° C. Afterstirring at this temperature for 30 minutes, 0.5 ml (4.38 mmoles)N-methylmorpholine are added, followed by a cold solution (-30° C.) of0.535 g (1.46 mmoles) H-Tyr-NH-NH-Z.HCl (65) and 0.16 ml (1.46 mmoles)N-methylmorpholine in 15 ml anhydrous dimethylformamide. The reactionmixture is allowed to react at -9° C. for three days, then the salts arefiltered off, the solvent is removed in vacuo, and the product is pouredinto 10% citric acid aqueous solution cooled to 0° C. The precipitate isfiltered, washed to neutrality with water and dried in vacuo. Theproduct is recrystallized from isopropyl alcohol-diethyl ether; 0.85 gof compound (66) are obtained, m.p. 137°-150° C.; [α]_(D) ²⁵ +3.8° (c=1,MeOH); Rf_(A) =0.27; Rf_(B) =0.52.

Step 4. H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Z.HCl (67)

Starting from 1.0 g (1.15 mmoles) Boc-Tyr-ala-Phe-Gly-Tyr-NH-NH-Z (66)and operating as in Step 2, compound (67) (0.83 g) is obtained fromethyl acetate: m.p. 190° C. (dec.); [α]_(D) ²⁵ +19.9° (c=1, MeOH);Rf_(C) =0.81; E₁.2 =0.59.

EXAMPLE 8 Preparation of H-Tyr-ala-Phe-Gly-NH-NH-Z.HCl (68)

Starting from 1.0 g (1.60 mmoles) Boc-Tyr-ala-Phe-Gly-NH-NH-Z (60), andoperating as in Step 8 of Example 6, 0.70 g of compound (68) areobtained from ethyl acetate, m.p. 215° C.; [α]_(D) ²³ +33.0° (c=1,MeOH); Rf_(C) =0.70; E₁.2 =0.62.

EXAMPLE 9 Preparation of H-Tyr-ala-Phe-Gly-NH-NH-CO-CH₂ -CH₂ -CH₃.HCl(70) Step 1. Boc-Tyr-ala-Phe-Gly-NH-NH-CO-CH₂ -CH₂ -CH₃ (69)

Starting from 0.12 ml (1.3 mmoles) butyric acid and 0.742 g (1.3 mmoles)Boc-Tyr-ala-Phe-Gly-NH-NH₂ (61), and operating as in Step 1 of Example6, 0.8 g of compound (69) are obtained from ethyl acetate; m.p. 125° C.(dec.), [α]_(D) ²⁵ +18.3° (c=1, MeOH); Rf_(C) =0.37.

Step 2. H-Tyr-ala-Phe-Gly-NH-NH-CO-CH₂ -CH₂ -CH₃.HCl (70)

Starting from 1.0 g (1.46 mmoles) Boc-Tyr-ala-Phe-Gly-NH-NH-CO-CH₂ -CH₂-C₃ (69) and operating as in Step 2 of Example 6, after purification bycolumn chromatography on silica gel and eluting withchloroform-methanol=9:1, 0.58 g of compound (70) are obtained fromisopropyl alcohol-diethyl ether; m.p. 215°-218° C. (dec.) [α]_(D) ²⁵+40.1° (c=1, MeOH); Rf_(C) =0.67, Rf_(D) =0.84; ₁.2 =0.75.

EXAMPLE 10 ##STR7## Step 1. Boc-Tyr-ala-Phe-Gly-NH-NH-tyr-Boc (71)

Starting from 1.0 (3.55 mmoles) Boc-tyr-OH and 2.03 g (3.55 mmoles)Boc-Tyr-ala-Phe-Gly-NH-NH₂ (60), and operating as in Step 1 of Example6, 2.3 g of compound (71) is obtained from ethyl acetate; m.p. 145°-150°C.; [α]_(D) ²⁵ +14.8° (c=1, MeOH); Rf_(A) =0.26 Rf_(B) =0.39.

Step 2. H-Tyr-ala-Phe-Gly-NH-NH-tyr-H.HCl (72)

Starting from 1.0 g (1.2 mmoles) Boc-Tyr-ala-Phe-Gly-NH-NH-tyr-Boc (71),and operating as in Step 2 of Example 6, 0.760 g of compound (72) areobtained from diethyl ether; m.p. 210°-215° C. (dec.); [α]_(D) ²⁵ +13.5°(c=1, MeOH); Rf_(C) =0.48; E₁.2 =0.84.

By the classical solution procedure the following derivatives have beensynthesized also:

(73) H-Tyr-ala-Phe-Gly-tyr-NHNH₂.2HCl m.p. 150°-155° C. (dec.) (ethylacetate); Rf_(C) =0.70

(74) Boc-Tyr-ala-Phe-Sar-NH-NH-Z

(75) H-Tyr-ala-Phe-Sar-Tyr-NH-NH-Z.HCl

(76) Boc-Tyr-ala-Phe-Sar-Tyr-NH-NH-Z

(77) H-Tyr-ala-Phe-Sar-Tyr-NH-NH-Boc.HCl

(78) Tfa-Tyr-ala-Phe-Sar-Tyr-NH-NH-Boc

(79) H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Ph.HCl

(80) Boc-Tyr-ala-Phe-Gly-Tyr-NH-NH-Ph

(81) H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Boc.HCl

(82) Tfa-Tyr-ala-Phe-Gly-Tyr-NH-NH-Boc

(83) H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Adoc.HCl

(84) Tfa-Tyr-ala-Phe-Gly-Tyr-NH-NH-Adoc

(85) H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Ad.HCl

(86) Boc-Tyr-ala-Phe-Gly-Tyr-NH-NH-Ad

(87) H-Tyr-ala-Phe-Gly-Leu-NH₂.HCl m.p. 143°-147° C. (isopropylalcohol-diethyl ether); [α]_(D) ²⁸ +8.1° (c=1, MeOH); Rf_(C) 0.73; E₁.20.62.

(88) H-Tyr-ala-Phe-Gly-Met-NH₂.HCl m.p. 220°0225° C. (isopropylalcohol-diisopropyl ether); [α]_(D) ²³ +13.5° (c=1, MeOH); Rf_(C) 0.68;E₁.2 0.63.

(89) H-Tyr-ala-Phe-Sar-Tyr-Pro-Ser-NH₂.HCl m.p. 195°-200° C. (dec.)(diethyl ether); Rf_(C) 0.49; E₁.2 0.49; [α]_(D) ²³ +18.0° (c=1, MeOH).

(90) H-Tyr-ala-Phe-Gly-Gly-Pro-Ser-NH₂.HCl m.p. 180° C. (dec.) (diethylether); [α]_(D) ²⁰ 0 (c=1, MeOH); Rf_(C) 0.32; E₁.2 0.58.

(91) H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NHMe. HCl m.p. 240° C. (dec.)(diethyl ether); [α]_(D) ²⁸ 0 (c=1, MeOH); Rf_(C) 0.55; E₁.2 0.52.

(92) H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NHEt. HCl m.p. 235° (dec.) (diethylether); [α]_(D) ²⁸ -3.54° (c=1, MeOH); Rf_(C) 0.62; E₁.2 0.52.

(93) H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-Ome. HCl m.p. 240° C. (dec.) (diethylether); [α]_(D) ²⁸ -4.5° (c=1, MeOH); Rf_(C) 0.66; E₁.2 0.55.

(94) H-Tyr-met-Phe-Gly-NHNHZ. HCl m.p. 140°-143° C. (CHCl₃ /diethylether); [α]_(D) ²⁸ -21.6° (c=1, DMF); Rf_(C) 0.79; E₁.2 0.54.

(95) H-Tyr-met(O)-Phe-Gly-NHNHZ. HCl m.p. 115°-120° C. (CHCl₃ /diethylether); [α]_(D) ²⁸ -23.2° (c=1, DMF); Rf_(C) 0.69; E₁.2 0.53.

(96) H-Tyr-ala-Phe-Gly-NHNHLrl. HCl m.p. 191°-198° C. (dec.) (isopropylalcohol-diethyl ether); [α]_(D) ²³ +46.0° (c=1, MeOH); Rf_(C) 0.84; E₁.20.41.

(97) H-Tyr-ala-Phe-Gly-NHNHBnl. HCl m.p. 254°-258° C. (dec.) (CH₃OH/CHCl₃ /ethyl acetate); [α]_(D) ²⁶ +41.4 (c=1, MeOH); Rf_(C) 0.79;E₁.2 0. 63.

(98) H-Tyr-ala-Phe-Gly-NHNH Adoc m.p. 142°-144° C. (dec.) (isopropylalcohol/diethyl ether); [α]_(D) ²³ +20.7 (c=1, MeOH); Rf_(C) 0.78; E₁.20.47.

(99) H-Tyr-ala-Phe-Gly-NHNHBoc m.p. 154° C. (dec.) (diethyl ether);Rf_(C) 0.79; E₁.2 0.60; [α]_(D) ²³ +27.9 (C=1, MeOH).

(100) H-Tyr-ala-Phe-Gly-Pro-NH₂. HCl

(101) H-Tyr-ala-Phe-Gly-Ser-NH₂. HCl

(102) H-Tyr-ala-Phe-Gly-tyr-NH₂. HCl

(103) H-Tyr-ala-Phe-Sar-Tyr-NH₂. HCl

(104) H-Tyr-met-Phe-Gly-Tyr-NH₂. HCl

(105) H-Tyr-met-Phe-Gly-Tyr-Pro-Ser-NH₂. HCl

(106) H-Tyr-ala-Phe-Pro-Tyr-Pro-Ser-NH₂. HCl

(107) H-Tyr-ala-Phe-MePhe-Tyr-Pro-Ser-NH₂. HCl

(108) H-Tyr-ala-Phe-MePhe-Tyr-Pro-Ser-OMe. HCl

(109) H-Tyr-ala-Phe-Gly-Tyr-Ppa-Ser-NH₂. HCl

(110) H-Tyr-ala-Phe-Gly-Tyr-Aze-Ser-NH₂. HCl

(111) H-Tyr-ala-Phe-Gly-Tyr-Tia-Ser-NH₂. HCl

(112) H-Tyr-ala-Phe-Gly-Tyr-ΔPr-Ser-NH₂. HCl

(113) H-Tyr-ala-Phe-Gly-Phe(NO₂)-Pro-Ser-NH₂. HCl

(114) H-Tyr-ala-Phe-Gly-Tyr-Pro-Abu-NH₂. HCl

(115) H-Tyr-ala-Phe-Gly-Tyr-Pro-Gly-NH₂. HCl

(116) H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Pro-Ser(Bzl)-NH₂. HCl

(117) H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser(Bzl)-NH₂. HCl

(118) H-Tyr-ala-Phe-Gly-Tyr-NH-Ad. HCl

(119) H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-OH. HCl

(120) H-Tyr-ala-Phe-Gly-Tyr-NH-CH₂ CF₃. HCl

(121) H-Tyr-met-Phe-Gly-NHNH₂. HCl

(122) H-Tyr-ala-Phe-Gly-tyr-NHNHZ. HCl

(123) H-Tyr-ala-Phe-Sar-Tyr-NHNHZ. HCl

In the above formulae

Me=CH₃,

Et=CH₂ CH₃,

Z=benzyloxycarbonyl,

Lrl=lauryl,

Bnl=benzoyl, and

Bzl=benzyl.

(124) H-Tyr-ala-Phe-Gly-Tyr-3allo Hyp-Ser-NH₂

(125) H-Tyr-ala-Phe-Gly-Pro-Ser-NH₂

(126) H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-NH₂

(127) H-Tyr-ala-Phe-Gly-Met(O)-NH₂

(128) H-Tyr-ala-Phe-Gly-Nva-NH₂

(129) H-Tyr-met-Phe-Gly-Pro-NH₂

(130) H-Tyr-met-Phe-Gly-Nva-NH₂

(131) H-Tyr-met(O)-Phe-Gly-Tyr-Pro-Ser-NH₂

(132) H-Tyr-ala-Phe-Ser-Tyr-Hyp-Ser-NH₂

(133) H-Tyr-ala-Phe-Sar-Tyr(Bzl)-Hyp-Ser(Bzl)-NH₂

(134) H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Ppa-Ser-NH₂

(135) H-Tyr-ala-Phe-Gly-Tyr-alloHyp-Ser-NH₂

(136) H-Tyr-ala-Phe-Gly-Tyr-3Hyp-Ser-NH₂

(137) H-Tyr-ala-Phe-Gly-Tyr(Bzl)-3Hyp-Ser(Bzl)-NH₂

(138) H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Aze-Ser-NH₂

(139) H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Tia-Ser-NH₂

(140) H-Tyr-ala-Phe-Gly-Tyr(Bzl)-ΔPr-Ser-NH₂

(141) H-Tyr-ala-Phe-Gly-Tyr-βAla-Ser-NH₂

(142) H-Tyr-ala-Phe-Gly-Phe(F)-Pro-Ser-NH₂

(143) H-Tyr-ala-Phe-Gly-Cha-Pro-Ser-NH₂

(144) H-Tyr-ala-Phe-Gly-Phg-Pro-Ser-NH₂

(145) H-Tyr-ala-Phe-Gly-Tyr (Me)-Pro-Ser-NH₂

(146) H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-CH(CH₃)₂

(147) H-Tyr-met(O)-Phe-Gly-NHNH₂

(148) H-Tyr-ala-Phe-Sar-Tyr-NHNH₂

(149) H-Tyr-ala-Phe-Phe-NH-NH-Z

(150) H-Tyr-ala-Phe-Phe-NH-NH₂

(151) H-Tyr-ala-Phe-Gly-Sar-Ser-NH₂

(152) Boc-Tyr-ala-Phe-Sar-NH-NH-Z

(153) H-Tyr-ala-Phe-Gly-Tyr-NH-NH₂

(154) H-Tyr-ala-Phe-Gly-Leu-NH-NH-Z

(155) H-Tyr-ala-Phe-Gly-Leu-NH-NH₂

(156) H-Tyr-ala-Phe-Gly-Tyr(Me)-Hyp-Ser-NH₂

(157) H-Tyr-ala-Phe-MePhe-Tyr-Pro-Ser-NH₂

(158) H-Tyr-ala-Phe-Gly-Tyr-MeAla-Ser-NH₂

(159) H-Tyr-ala-Phe-Tyr(Bzl)-alloHyp-Ser(Bzl)-NH₂

(160) H-Tyr-ala-Phe-MePhe-Tyr-Pro-Ser-OH

(161) H-Tyr-ala-Phe-Sar-Tyr(Bzl)-Pro-Ser-NH₂

(162) H-Tyr-ala-Phe-Pro-Tyr(Bzl)-Pro-Ser-NH₂

(163) H-Tyr-ala-Phe-Pro-Tyr-Hyp-Ser-NH₂

(164) H-Tyr-ala-Phe-Pro-Tyr(Bzl)-Hyp-Ser(Bzl)-NH₂

In the above formulae,

Cha=hexahydrophenylalanine,

Phg=phenylglycine,

Phe(F)=p-fluorophenylalanine,

met(O)=D-methionine sulphoxide,

MePhe=N-methylphenylalanine,

Ppa=pipecolic acid,

Aze=2-azetidine carboxylic acid,

Tia=4-tiazolidine carboxylic acid,

ΔPr= ##STR8##

Phe(NO₂)=p-nitro-phenylalanine,

Abu=α-amino-n-butyric acid,

Tyr(Bzl)-tyrosine O-benzyl ether, and

Ser(Bzl)-serine O-benzyl ether.

All of the listed compounds were synthesized either by the classicalsolution procedure or by the solid phase.

What is claimed is:
 1. A biologically active peptide selected from thegroup consisting ofH-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr-NH₂, H-Tyr-ala-Phe-Gly-OMe, H-Tyr-ala-Phe-Gly-OH,H-Tyr-ala-Phe-Gly-NH₂, H-Tyr-ala-Phe-Gly-NH-NH₂,H-Tyr-ala-Phe-Sar-NH-NH₂, H-Tyr-ala-Phe-Sar-NH-NH-Z,Boc-Tyr-ala-Phe-Sar-NH-NH₂, Boc-Tyr-ala-Phe-Phe-NH-NH₂,H-Tyr-ala-Phe-Gly-Tyr-Pro-NH₂, H-Tyr-ala-Phe-Gly(Bzl)-Pro-NH₂,Boc-Tyr-ala-Phe-Gly-Tyr-Pro-NH₂, Boc-Tyr-ala-Phe-Gly-Tyr(Bzl)-Pro-NH₂,H-Tyr-ala-Phe-Gly-Tyr-Ser-NH₂, Boc-Tyr-ala-Phe-Gly-Tyr-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr-Hyp-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Hyp-Ser(Bzl)-NH₂,Boc-Tyr-ala-Phe-Gly-Tyr-Hyp-Ser-NH₂,Boc-Tyr-ala-Phe-Gly-Tyr(Bzl)-Hyp-Ser(Bzl)-NH₂,H-Tyr-ala-Phe-Gly-Tyr-Val-Ser-NH₂, Boc-Tyr-ala-Phe-Gly-Tyr-Val-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr-Gly-Ser-NH₂, Boc-Tyr-ala-Phe-Gly-Tyr-Gly-Ser-NH₂,H-Tyr-ala-Phe-Gly-Phe-Pro-Ser-NH₂, Boc-Tyr-ala-Phe-Gly-Phe-Pro-Ser-NH₂,H-Tyr-ala-Phe-Gly-Phe-Hyp-Ser-NH₂,H-Tyr-ala-Phe-Gly-Phe-Hyp-Ser(Bzl)-NH₂,Boc-Tyr-ala-Phe-Gly-Phe-Hyp-Ser-NH₂,Boc-Tyr-ala-Phe-Gly-Phe-Hyp-Ser(Bzl)-NH₂,H-Tyr-ala-Phe-Gly-Trp-Pro-Ser-NH₂, Boc-Tyr-ala-Phe-Gly-Trp-Pro-Ser-NH₂,H-Tyr-ala-Phe-Phe-Tyr-Pro-Ser-NH₂,H-Tyr-ala-Phe-Phe-Tyr(Bzl)-Pro-Ser-NH₂,Boc-Tyr-ala-Phe-Phe-Tyr-Pro-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-NH-Z, H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Z,H-Tyr-ala-Phe-Gly-NH-NH-Z, H-Tyr-ala-Phe-Gly-NH-NH-CO-CH₂ -CH₂ -CH₃,H-Tyr-ala-Phe-Gly-NH-NH-tyr-H, H-Tyr-ala-Phe-Sar-NH-NH-Z,Boc-Tyr-ala-Phe-Sar-NH-NH-Z, H-Tyr-ala-Phe-Sar-Tyr-NH-NH-Z,Boc-Tyr-ala-Phe-Sar-Tyr-NH-NH-Z, H-Tyr-ala-Phe-Sar-Tyr-NH-NH-Boc,Tfa-Tyr-ala-Phe-Sar-Tyr-NH-NH-Boc, H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Ph,Boc-Tyr-ala-Phe-Gly-NH-NH-Ph, H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Boc,Tfa-Tyr-ala-Phe-Gly-Tyr-NH-NH-Boc, H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Adoc,Tfa-Tyr-ala-Phe-Gly-Tyr-NH-NH-Adoc, H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Ad,Boc-Tyr-ala-Phe-gly-NH-NH-Ad, H-Tyr-ala-Phe-Gly-Leu-NH₂,H-Tyr-ala-Phe-Gly-Met-NH₂, H-Tyr-ala-Phe-Sar-Tyr-Pro-Ser-NH₂,H-Tyr-ala-Phe-Gly-Gly-Pro-Ser-NH₂, H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NHMe,H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NHEt, H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-OMe,H-Tyr-met-Phe-Gly-NHNHZ, H-Tyr-met(O)-Phe-Gly-NHNHZ,H-Tyr-ala-Phe-Gly-NHNHLrl, H-Tyr-ala-Phe-Gly-MHNHBnl,H-Tyr-ala-Phe-Gly-tyrNHNH₂, H-Tyr-ala-Phe-Gly-NHNHAdoc,H-Tyr-ala-Phe-Gly-NHNHBoc, H-Tyr-ala-Phe-Gly-Pro-NH₂,H-Tyr-ala-Phe-Gly-Ser-NH₂, H-Tyr-ala-Phe-Gly-tyr-NH₂,H-Tyr-ala-Phe-Sar-Tyr-NH₂, H-Tyr-ala-Phe-Gly-Tyr-Sar-Ser-NH₂H-Tyr-ala-Phe-Gly-Pro-Ser-NH₂, H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-NH₂,H-Tyr-met-Phe-Gly-Tyr-NH₂, H-Tyr-met-Phe-Gly-Tyr-Pro-Ser-NH₂,H-Tyr-ala-Phe-Pro-Tyr-Pro-Ser-NH₂, H-Tyr-ala-Phe-MePhe-Tyr-Pro-Ser-OMe,H-Tyr-ala-Phe-Gly-Tyr-Ppa-Ser-NH₂, H-Tyr-ala-Phe-Gly-Tyr-Aze-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr-Tia-Ser-NH₂, H-Tyr-ala-Phe-Gly-Tyr-ΔPr-Ser-NH₂,H-Tyr-ala-Phe-Gly-Phe(NO₂)-Pro-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr-Pro-Abu-NH₂, H-Tyr-ala-Phe-Tyr-Pro-Gly-NH₂,H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Pro-Ser(Bzl)-NH₂,H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser(Bzl)-NH₂, H-Tyr-ala-Phe-Gly-Tyr-NH-Ad,H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-OH, H-Tyr-ala-Phe-Gly-Tyr-NH-Ch₂ CF₃,H-Tyr-ala-met-Phe-Gly-NHNH₂, H-Tyr-ala-Phe-Gly-tyr-NHNHZ,H-Tyr-ala-Phe-Gly-Met(O)-NH₂, H-Tyr-ala-Phe-Gly-Nva-NH₂,H-Tyr-met-Phe-Gly-Pro-NH₂, H-Tyr-met-Phe-Gly-Nva-NH₂,H-Tyr-met(O)-Phe-Gly-Tyr-Pro-Ser-NH₂, H-Tyr-ala-Phe-Sar-Tyr-Hyp-Ser-NH₂,H-Tyr-ala-Phe-Sar-Tyr(Bzl)-Hyp-Ser(Bzl)-NH₂,H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Ppa-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr-alloHyp-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr-3Hyp-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr(Bzl)-3-Hyp-Ser(Bzl)-NH₂,H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Aze-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Tia-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr(Bzl)-ΔPr-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr-βAla-Ser-NH₂,H-Tyr-ala-Phe-Gly-Phe(F)-Pro-Ser-NH₂, H-Tyr-ala-Phe-Gly-Cha-Pro-Ser-NH₂,H-Tyr-ala-Phe-Gly-Phg-Pro-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr(Me)-Pro-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-CH(CH₃)₂, H-Tyr-met(O)-Phe-Gly-NHNH₂,H-Tyr-ala-Phe-Sar-Tyr-NHNH₂, H-Tyr-ala-Phe-Phe-NH-NH₂,H-Tyr-ala-Phe-MePhe-Tyr-Pro-Ser-NH₂,H-Tyr-ala-Phe-Gly-Tyr-MeAla-Ser-NH₂, H-Tyr-ala-Phe-Phe-NH-NHZ,H-Tyr-ala-Phe-Gly-Tyr-NH-NH₂, H-Tyr-ala-Phe-Gly-Leu-NH-NHZ,H-Tyr-ala-Phe-Gly-Tyr(Me)-Hyp-Ser-NH₂,H-Tyr-ala-Phe-Tyr(Bzl)-alloHyp-Ser-(Bzl)-NH₂,H-Tyr-ala-Phe-MePhe-Tyr-Pro-Ser-OH,H-Tyr-ala-Phe-Sar-Tyr(Bzl)-Pro-Ser-NH₂,H-Tyr-ala-Phe-Pro-Tyr(Bzl)-Pro-Ser-NH₂,H-Tyr-ala-Phe-Pro-Tyr-Hyp-Ser-NH₂,H-Tyr-ala-Phe-Pro-Tyr(Bzl)-Hyp-Ser(Bzl)-NH₂, andH-Tyr-ala-Phe-Gly-Tyr-3alloHyp-Ser-NH₂,and a pharmaceutically acceptablesalt thereof.
 2. A compound as defined in claim 1, wherein in peptide isH-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH₂.
 3. A compound as defined in claim 1,wherein the peptide is H-Tyr-ala-Phe-Gly-Tyr-NH₂.
 4. A compound asdefined in claim 1, wherein the peptide is H-Tyr-ala-Phe-Gly-OMe.
 5. Acompound as defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Gly-OH.
 6. A compound as defined in claim 1, wherein thepeptide is H-Tyr-ala-Phe-Gly-NH₂.
 7. A compound as defined in claim 1,wherein the peptide is H-Tyr-ala-Phe-Gly-NH-NH₂.
 8. A compound asdefined in claim 1, wherein the peptide is H-Tyr-ala-Phe-Sar-NH-NH₂. 9.A compound as defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Sar-NH-NH-Z.
 10. A compound as defined in claim 1, whereinthe peptide is Boc-Tyr-ala-Phe-Sar-NH-NH₂.
 11. A compound as defined inclaim 1, wherein the peptide is Boc-Tyr-ala-Phe-Phe-NH-NH₂.
 12. Acompound as defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Gly-Tyr-Pro-NH₂.
 13. A compound as defined in claim 1,wherein the peptide is H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Pro-NH₂.
 14. Acompound as defined in claim 1, wherein the peptide isBoc-Tyr-ala-Phe-Gly-Tyr-Pro-NH₂.
 15. A compound as defined in claim 1,wherein the peptide is Boc-Tyr-ala-Phe-Gly-Tyr(Bzl)-Pro-NH₂.
 16. Acompound as defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Gly-Tyr-Ser-NH₂.
 17. A compound as defined in claim 1,wherein the peptide is Boc-Tyr-ala-Phe-Gly-Tyr-Ser-NH₂.
 18. A compoundas defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Gly-Tyr-Hyp-Ser-NH₂.
 19. A compound as defined in claim 1,wherein the peptide is H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Hyp-Ser(Bzl)-NH₂. 20.A compound as defined in claim 1, wherein the peptide isBoc-Tyr-ala-Phe-Gly-Tyr-Hyp-Ser-NH₂.
 21. A compound as defined in claim1, wherein the peptide is Boc-Tyr-ala-Phe-Gly-Tyr(Bzl)-Hyp-Ser(Bzl)-NH₂.22. A compound as defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Gly-Tyr-Val-Ser-NH₂.
 23. A compound as defined in claim 1,wherein the peptide is Boc-Tyr-ala-Phe-Gly-Tyr-Val-Ser-NH₂.
 24. Acompound as defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Gly-Tyr-Gly-Ser-NH₂.
 25. A compound as defined in claim 1,wherein the peptide is Boc-Tyr-ala-Phe-Gly-Tyr-Gly-Ser-NH₂.
 26. Acompound as defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Gly-Phe-Pro-Ser-NH₂.
 27. A compound as defined in claim 1,wherein the peptide is Boc-Tyr-ala-Phe-Gly-Phe-Pro-Ser-NH₂.
 28. Acompound as defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Gly-Phe-Hyp-Ser-NH₂.
 29. A compound as defined in claim 1,wherein the peptide is H-Tyr-ala-Phe-Gly-Phe-Hyp-Ser(Bzl)-NH₂.
 30. Acompound as defined in claim 1, wherein the peptide isBoc-Tyr-ala-Phe-Gly-Phe-Hyp-Ser-NH₂.
 31. A compound as defined in claim1, wherein the peptide is Boc-Tyr-ala-Phe-Gly-Phe-Hyp-Ser(Bzl)-NH₂. 32.A compound as defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Gly-Trp-Pro-Ser-NH₂.
 33. A compound as defined in claim 1,wherein the peptide is Boc-Tyr-ala-Phe-Gly-Trp-Pro-Ser-NH₂.
 34. Acompound as defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Phe-Tyr-Pro-Ser-NH₂.
 35. A compound as defined in claim 1,wherein the peptide is H-Tyr-ala-Phe-Phe-Tyr(Bzl)-Pro-Ser-NH₂.
 36. Acompound as defined in claim 1, wherein the peptide isBoc-Tyr-ala-Phe-Phe-Tyr-Pro-Ser-NH₂.
 37. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-NH-Z.
 38. Thecompound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-NH-NH-Z.
 39. The compound of claim 1, wherein saidpeptide is H-Tyr-ala-Phe-Gly-NH-NH-Z.
 40. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-NH-NH-CO-CH₂ -CH₂ -CH₃. 41.The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-NH-NH-tyr-H.
 42. The compound of claim 1, wherein saidpeptide is H-Tyr-ala-Phe-Sar-NH-NH-Z.
 43. The compound of claim 1,wherein said peptide is Boc-Tyr-ala-Phe-Sar-NH-NH-Z.
 44. The compound ofclaim 1, wherein said peptide is H-Tyr-ala-Phe-Sar-Tyr-NH-NH-Z.
 45. Thecompound of claim 1, wherein said peptide isBoc-Tyr-ala-Phe-Sar-Tyr-NH-NH-Z.
 46. The compound of claim 1, whereinsaid peptide is H-Tyr-ala-Phe-Sar-Tyr-NH-NH-Boc.
 47. The compound ofclaim 1, wherein said peptide is Tfa-Tyr-ala-Phe-Sar-Tyr-NH-NH-Boc. 48.The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-NH-NH-Ph.
 49. The compound of claim 1, whereinsaid peptide is Boc-Tyr-ala-Phe-Gly-Tyr-NH-NH-Ph.
 50. The compound ofclaim 1, wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Boc. 51.The compound of claim 1, wherein said peptide isTfa-Tyr-ala-Phe-Gly-Tyr-NH-NH-Boc.
 52. The compound of claim 1, whereinsaid peptide is H-Tyr-ala-Phe-Gly-Tyr-NH-NH-Adoc.
 53. The compound ofclaim 1, wherein said peptide is Tfa-Tyr-ala-Phe-Gly-Tyr-NH-NH-Adoc. 54.The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-NH-NH-Ad.
 55. The compound of claim 1, whereinsaid peptide is Boc-Tyr-ala-Phe-Gly-Tyr-NH-NH-Ad.
 56. The compound ofclaim 1, wherein said peptide is H-Tyr-ala-Phe-Gly-Leu-NH₂.
 57. Thecompound of claim 1, wherein said peptide is H-Tyr-ala-Phe-Gly-Met-NH₂.58. The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Sar-Tyr-Pro-Ser-NH₂.
 59. The compound of claim 1, whereinsaid peptide is H-Tyr-ala-Phe-Gly-Gly-Pro-Ser-NH₂.
 60. The compound ofclaim 1, wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NHMe. 61.The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NHEt.
 62. The compound of claim 1, whereinsaid peptide is H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-OMe.
 63. The compound ofclaim 1, wherein said peptide is H-Tyr-met-Phe-Gly-NHNHZ.
 64. Thecompound of claim 1, wherein said peptide is H-Tyr-met(O)-Phe-Gly-NHNHZ.65. The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-NHNHLrl.
 66. The compound of claim 1, wherein saidpeptide is H-Tyr-ala-Phe-Gly-NHNHBnl.
 67. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-tyrNHNH₂.
 68. The compound ofclaim 1, wherein said peptide is H-Tyr-ala-Phe-Gly-NHNHAdoc.
 69. Thecompound of claim 1, wherein said peptide is H-Tyr-ala-Phe-Gly-NHNHBoc.70. The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Pro-NH₂.
 71. The compound of claim 1, wherein saidpeptide is H-Tyr-ala-Phe-Gly-Ser-NH₂.
 72. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-tyr-NH₂.
 73. The compound ofclaim 1, wherein said peptide is H-Tyr-ala-Phe-Sar-Tyr-NH₂.
 74. Thecompound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-Sar-Ser-NH₂.
 75. The compound of claim 1, whereinsaid peptide is H-Tyr-ala-Phe-Gly-Pro-Ser-NH₂.
 76. The compound of claim1, wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-NH₂.
 77. Thecompound of claim 1, wherein said peptide is H-Tyr-met-Phe-Gly-Tyr-NH₂.78. The compound of claim 1, wherein said peptide isH-Tyr-met-Phe-Gly-Tyr-Pro-Ser-NH₂.
 79. The compound of claim 1, whereinsaid peptide is H-Tyr-ala-Phe-Pro-Tyr-Pro-Ser-NH₂.
 80. The compound ofclaim 1, wherein said peptide is H-Tyr-ala-Phe-MePhe-Tyr-Pro-Ser-OMe.81. The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-Ppa-Ser-NH₂.
 82. The compound of claim 1, whereinsaid peptide is H-Tyr-ala-Phe-Gly-Tyr-Aze-Ser-NH₂.
 83. The compound ofclaim 1, wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-Tia-Ser-NH₂. 84.The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-ΔPr-Ser-NH₂.
 85. The compound of claim 1, whereinsaid peptide is H-Tyr-ala-Phe-Gly-Phe(NO₂)-Pro-Ser-NH₂.
 86. The compoundof claim 1, wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-Pro-Abu-NH₂.87. The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-Pro-Gly-NH₂.
 88. The compound of claim 1, whereinsaid peptide is H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Pro-Ser(Bzl)-NH₂.
 89. Thecompound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-Pro-Ser(Bzl)-NH₂.
 90. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-NH-Ad.
 91. The compound ofclaim 1, wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-OH. 92.The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-NH-CH₂ CF₃.
 93. The compound of claim 1, whereinsaid peptide is H-Tyr-met-Phe-Gly-NHNH₂.
 94. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-tyr-NHNHZ.
 95. The compound ofclaim 1, wherein said peptide is H-Tyr-ala-Phe-Gly-Met(O)-NH₂.
 96. Thecompound of claim 1, wherein said peptide is H-Tyr-ala-Phe-Gly-Nva-NH₂.97. The compound of claim 1, wherein said peptide isH-Tyr-met-Phe-Gly-Pro-NH₂.
 98. The compound of claim 1, wherein saidpeptide is H-Tyr-met-Phe-Gly-Nva-NH₂.
 99. The compound of claim 1,wherein said peptide is H-Tyr-met(O)-Phe-Gly-Tyr-Pro-Ser-NH₂.
 100. Thecompound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Sar-Tyr-Hyp-Ser-NH₂.
 101. The compound of claim 1, whereinsaid peptide is H-Tyr-ala-Phe-Sar-Tyr(Bzl)-Hyp-Ser(Bzl)-NH₂.
 102. Thecompound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr(Bzl)-Ppa-Ser-NH₂.
 103. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-alloHyp-Ser-NH₂.
 104. Thecompound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-3Hyp-Ser-NH₂.
 105. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr(Bzl)-3Hyp-Ser(Bzl)-NH₂.106. The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr(Bzl)-Aze-Ser-NH₂.
 107. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr(Bzl)-Tia-Ser-NH₂.
 108. Thecompound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr(Bzl)-ΔPr-Ser-NH₂.
 109. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-βAla-Ser-NH₂.
 110. Thecompound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Phe(F)-Pro-Ser-NH₂.
 111. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-Cha-Pro-Ser-NH₂.
 112. Thecompound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Phg-Pro-Ser-NH₂.
 113. The compound of claim 1, whereinsaid peptide is H-Tyr-ala-Phe-Gly-Tyr(Me)-Pro-Ser-NH₂.
 114. The compoundof claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr-Pro-Ser-NH-CH(CH₃)₂.
 115. The compound of claim 1,wherein said peptide is H-Tyr-met(O)-Phe-Gly-NHNH₂.
 116. The compound ofclaim 1, wherein said peptide is H-Tyr-ala-Phe-Sar-Tyr-NHNH₂.
 117. Thecompound of claim 1, wherein said peptide is H-Tyr-ala-Phe-Phe-NH-NH₂.118. The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-MePhe-Tyr-Pro-Ser-NH₂.
 119. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-MeAla-Ser-NH₂.
 120. Acompound defined in claim 1, wherein the peptide isH-Tyr-ala-Phe-Phe-NH-NHZ.
 121. The compound of claim 1, wherein saidpeptide is H-Tyr-ala-Phe-Gly-Tyr-NH-NH₂.
 122. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-Leu-NH-NHZ.
 123. The compoundof claim 1, wherein said peptide isH-Tyr-ala-Phe-Gly-Tyr(Me)-Hyp-Ser-NH₂.
 124. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Tyr(Bzl)-alloHyp-Ser(Bzl)-NH₂.125. The compound of claim 1, wherein said peptide isH-Tyr-ala-Phe-MePhe-Tyr-Pro-Ser-OH.
 126. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Sar-Tyr(Bzl)-Pro-Ser-NH₂.
 127. Thecompound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Pro-Tyr(Bzl)-Pro-Ser-NH₂.
 128. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Pro-Tyr-Hyp-Ser-NH₂.
 129. Thecompound of claim 1, wherein said peptide isH-Tyr-ala-Phe-Pro-Tyr(Bzl)-Hyp-Ser(Bzl)-NH₂.
 130. The compound of claim1, wherein said pharmacentically acceptable salt is selected from thegroup consisting of trifluoroacetic acid, hydrofluoric acid, hydroboricacid, acetic acid, and hydrochloric acid.
 131. The compound of claim 1,wherein said peptide is H-Tyr-ala-Phe-Gly-Tyr-3alloHyp-Ser-NH₂.